Many oncogenes such as Ras induce senescence-like phenotypes termed oncogene-induced senescence (OIS). It is well established that OIS is a barrier of tumorigenesis, and OIS has to be suppressed for cells to be transformed by oncogenes. However, how OIS is suppressed during cell transformation remains unclear. In addition to suppressing OIS, oncogenes have to reprogram cellular metabolism to glycolysis to facilitate tumorigenesis and cancer progression. One of the major mechanism by which Ras induce metabolic reprograming is through upregulation of hypoxia-inducible factor 1 (HIF1). It is also unclear how Ras upregulates HIF1. We recently found that the E3 ubiquitin ligase subunit WSB1 plays a role in suppressing OIS and promoting metabolic reprogramming downstream of Ras. WSB1 is overexpressed in several human cancers including breast cancer, pancreatic cancer and melanoma. We show that WSB1 is upregulated by oncogenic Ras and Myc, and expression of WSB1 in primary MEFs expressing oncogenic Ras contributes to the suppression of OIS, leading to abnormal proliferation and cell transformation. Conversely, WSB1 downregulation promotes OIS. Mechanistically, we found that WSB1 negatively regulates ATM, which is important for inducing OIS. In addition, we found that WSB1 upregulates HIF1? and promotes metabolic phenotypes consistent with increased glycolysis. We hypothesize that WSB1 is a key player in early oncogenic events to i) suppress the DNA damage response and OIS through ATM degradation and ii) promote metabolic reprogramming through the HIF1 pathway. To test this hypothesis, we propose the following specific aims: 1. Study the regulation of ATM, the DNA damage response and OIS by WSB1;2. Study the regulation of HIF1? by WSB1;3. Generate WSB1 knockout mice to study the role of WSB1 in cancer development and progression. These studies will elucidate both a new factor that contributes to Ras induced tumorigenesis and a novel mechanism by which OIS is suppressed and metabolic reprogramming is induced. Because oncogenic Ras plays an important role in tumorigenesis in a variety of human cancers, our study will have significant impact on current understanding of the cause and progression of human cancer.

Public Health Relevance

Ras is abnormally activated in many human cancers and is a driver for tumorigenesis. How Ras induces tumors remains unclear. We have found that WSB1 is a downstream effector of WSB1 and based on our initial studies, we hypothesize that WSB1 contributes to tumorigenesis through its effect on cell cycle progression and cellular energy metabolism. We will study how the Ras-WSB1 signaling pathway can overcome barriers for tumorigenesis and remodel cellular energy metabolism. We will also use animal models to study how WSB1 contributes to tumorigenesis in organisms. Understanding of this signaling pathway will have profound and wide application in human cancers with Ras mutations.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Pelroy, Richard
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Mayo Clinic, Rochester
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